N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide is a known inhibitor of metalloproteinase and TNF and is therefore believed to be a potent therapeutic strategy for the treatment of inflammatory, infectious, immunological or malignant diseases including, but not limited to, septic shock, haemodynamic shock, sepsis syndrome, post ischarmic reperfusion injury, malaria, mycobacterial infection, meningitis, congestive heart failure, cancer and the like as disclosed in Baxter et al. (U.S. Pat. No. 5,981,490), incorporated herein by reference.
N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide has been prepared by reacting 1,5,5-trimethyl-3-((3S)-thiobenzoyl-3-carboxypropyl)hydantoin with L-leucyl-L-tert-leucine N-methylamide in the presence of a coupling reagent to produce the intermediate compound N-[(2S)-thiobenzoyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide which is converted to the desired N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide. The reaction to form the intermediate compound has been previously conducted in a non-aqueous environment resulting in the formation of the intermediate compound (N-[(2S)-thiobenzoyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide) as well as undesirable impurities including those indicated below:
N-[(2R)-thiobenzoyl-4-(1,5,5,-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide;
    Isobutoxycarbonyl-L-leucyl-L-tert-leucine N-methylamide;    2-thiobenzoyl-4-(1,5,5-trimethylhydantoinyl)butanoyl-iso-butanoate; and    2-thiobenzoyl-4-(1,5,5-trimethylhydantoinyl)butanoyl anhydride.
The presence of these impurities reduces the yield of the desired intermediate and increases the cost associated with the production of the end product N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide.
It would therefore be a significant advance in the art of producing N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide to provide a process for production which reduces the presence of impurities during production of the intermediate N-[(2S)-thiobenzoyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide to thereby increase the yield of the intermediate compound as well as the desired N-[(2S)-sulfanyl-4-(1,5,5-trimethylhydantoinyl)butanoyl]-L-leucyl-L-tert-leucine N-methylamide.